Ismail El-Hamamsy, MD, PhD, Professor of Cardiovascular Surgery, discusses the latest in aortic valve surgery in non-elderly adults, and reviews what is new in the literature on this topic. Presented on July 21, 2020, this Grand Rounds presentation from the Department of Medicine, Division of Cardiology, at the Icahn School of Medicine at Mount Sinai will enable viewers to:
1. Appreciate the dynamic anatomy of the aortic root
2. Recognize the unique challenges in young adults with aortic valve disease 3. Identify the optimal options for non-elderly patients needing aortic valve interventions 4. Appreciate the specific role of reconstructive valve procedures in this patient population (AV repair and Ross procedure)
Thank you so much for showing up this morning for this for these grand rounds. Um, this morning I will talk about aortic valve surgery in non elderly adults, and I will show you what is new in the literature, particularly over the last decade or so. I have no disclosures relevant to this presentation. These are the two case scenarios that I want to discuss this morning. The first is a 53 year old patient previous smoker with severe aortic stenosis. A normal ejection fraction. You can see the aortic valve is bicuspid. It is very heavily calcified. And the aortic aneurysm seems rather normal size and the other patient is slightly younger, 36 years old. With no previous medical history, a bike has been aortic valve with severe aortic regurgitation and it dilated aorta cruise. Now, the focus of this presentation this morning, as you saw from these two case scenarios are non elderly adults and these air, slightly different from the elderly patient population that we regularly operate on or now undergoing tab are in that they have a much higher level of physical activity. Quality of life is obviously important for all our patients But in non elderly patients, it is particularly important as they're still professionally active. Personally, they usually have. You know, they often have young families and they're physically active and they want to play sports. So all of these things have to be taken into account when considering what options are optimal for a patient. But more importantly, they all have a prolonged anticipated life expectancy versus elderly patients. And that translates into a longer exposure to potential valve related complications, whether that be degeneration and re operation with a tissue valve, or whether that is bleeding and thrombin embolism with a mechanical valve. And so the first point that I want to bring to you this morning is that conventional aortic valve replacement in non elderly adults using mechanical or tissue valves is associated with excess long term mortality. But before I do so, let's just remember there are several advantages in using a mechanical or a tissue out there very standardized operations. They can be performed in all hospitals offering cardiac surgery there very easily reproducible operations. They're very short operations, and importantly, we have long term data to support their use. That being said when we look at the long term data. The data is very positive, particularly for elderly patients, but it's slightly more sobering when we focus on these non elderly patients. This is a Swedish study in Sweden is very particular in that all patients undergoing cardiac surgery are placed into a national database and followed over the long term, which allows us to have long term information about the impact of any cardiac operation that patients undergo. So what they did is they looked at observed versus relative survival of patients after aortic valve replacement using a mechanical or a tissue valve substitute. And what they showed is that in the black dots, the observed mortality of the patients was significantly higher than the expected survival in the age and sex matched general population. And you can see that the curves start to significantly diverge about 7 to 8 years after the operation. So there is excess mortality after aortic valve replacement. Now, if I show you these scarce, I'm sure that the majority of you in the room right now are thinking this is probably driven by older patients because maybe they have more calm abilities and are dying faster except the authors actually stratified the patients according to their age at the time of surgery. And what they showed looking at observed versus expected ratios of death is that younger patients those under the age of 50 had the highest oe ratio as opposed to the older patients. So Anno e ratio of 4.5 in patients under 50 versus an oe ratio of one for patients over the age of 70. In other words, over the age of 70 survival is restored to that of the general population. But in younger patients, the mortality significantly higher than one would expect in the general population for patients for individuals that do not have aortic valve disease. So, in other words, the younger the patients are at the time of surgery, the higher that excess mortality is in the long term. It may sound counterintuitive because oftentimes we think that we're curing the disease when we're replacing the valve with a tissue or mechanical valve. But the data does not seem to support this theory. This is another study from my previous group in Montreal, where we analyzed outcomes of mechanical aortic valve replacement in non elderly adults in patients undergoing isolated elective aortic valve replacement over 450 consecutive patients under the age of 65. And we excluded anything that we thought may have an impact on long term outcomes. Patients undergoing concomitant procedures, those with coronary artery disease, re operations, emergency surgeries, dissections, endocarditis. We really kept it down to isolated aortic valve disease. The mean age of the patients was 53 so exactly similar to the case scenario I showed you at the beginning of this presentation, and the mean follow up was nine years and was 95% complete. So pretty robust data in terms of durability. And what we saw was that survival of these patients at 10 years was significantly lower than the age and sex matched general population. And that gap is, you can see continued to increase up to 15 years after surgery. Importantly, when we combine re operation, which is a rare event but still exists after mechanical, a VR with mortality survival free from the operate from re operation at 10 years was only 82% in this cohort. In other words, at 10 years, one in five patients was either dead or re operated after elective isolated mechanical aortic valve replacement. Pretty sobering data, considering these patients are all followed in anti coagulation clinics with very good follow up. Well, 1 may argue that mechanical valves air now less and less used, and we're moving towards biological solutions, which is a fact. But how do tissue aortic valve replacement perform inpatient and young patients? Well, this is a study from the Cleveland Clinic looking at over 3000 consecutive patients undergoing tissue A VR, and their conclusions were rather similar. Younger patients had worse than expected survival that was further diminished with insertion of a small prosthesis. So introducing the notion off patient prosthesis mismatch and its impact, as we will see in just a bit in non elderly adults. This is another very large study from a French group by Terry Begin in one of our former fellows looking at over 2500 patients undergoing biological aortic valve replacement in France, and what they did is stratified the patients according to their age at the time of surgery. And in black, you see the observed survival of these patients, and in gray you see the expected survival in the age and sex match French population and again similar to the Swedish study. Older patients over the age of 70 had observed and expected survival that were almost similar. But younger patients, particularly under the age of 50 and even under the age of 60 had observed survival in black. That was significantly lower than the expected survival in the general population. So we're definitely there are years of life being amputated by placing a prosthetic aortic valve in the Arctic position. Now, newer generations of tissue valves seem to be more durable, and that's great news for patients. In fact, if we look at this study focusing on patients between the age of 50 and 65 on looking at the median durability of these biological prosthesis, you can see that the median durability is about 18.5 years after a tissue, A VR, which sounds like a great proposition if you're if we're talking about a 55 year old patient, well, if we can tell them that this valve will last almost 20 years and then they can have a valve valve procedure that sounds like we found the solution for these patients. But what I want to try to say here, especially for the fellows and residents in the room, is that we cannot associate structural values generation from re operation structure. Of that degeneration and death are competing risks. If you are dead, you will never have structure of love, the generation. In fact, in all of the actuarial curves, your valve will be a very durable option. And if we look at that same study survival, almost 50% of the patients were already dead. At 15 years. These patients will not have s VD, which enhances the longevity of these prosthetic valves. So there's a grain of salt that needs to be put when analyzing or interpreting some of these durability data. And finally, this study coming from the State of California, which was recently published in New England Journal looking at 10,000 consecutive isolated aortic valve replacements, uh, in patients under the age of 65. And what they showed is by stratify ing the patients between age 50 45 54 a 15 year mortality of 26 30% If the patients under goat underwent a mechanical or a tissue aortic valve replacement and in patients aged 55 to 60 for a 15 year mortality of 32 to 36%. So, in other words, one in 321 in four patients were dead 15 years after surgery after undergoing isolated aortic valve replacement in patients under the age of 65. Again, very sobering data in that this is far from being the results that we would expect anticipate or hope for in our patients after isolated aortic valve replacement. So it's submit to you that conventional aortic valve replacement in the young it's far from being a curative procedure. It is, at best, a palliative procedure, and that's why we need to try to find better options to address this problem in young adults. Now, why is it that mortality in the long term is higher than one would expect in the general population after the valve has been replaced? I think the answer is twofold. One is human dynamics and second is biology, and the first point that I want to bring about is to think ppm. As I mentioned in that Cleveland Clinic paper, patients that had a higher grade e int or more or smaller prosthesis had higher mortality in the long term, and that is particularly significant because we know that patient prosthesis mismatch after, UH, aortic valve replacement is a very prevalent problem. About 40 to 45% of patients leaving the hospital leave with either moderate or severe mismatched, as shown in this recent review by Catherine Auto. Um, but importantly, the impact off patient prosthesis mismatch is particularly significant in younger patients those under the age of 70. As you can see from this Pebereau study, looking at overall survival after aortic valve replacement, survival was significantly diminished when severe mismatch was present in younger patients, but not so much so when it was present in patients over the age of 70. With the advent of tab, our patient prosthesis mismatch is thought to become a thing of the past because these vows are not mounted on a rigid, so sewing ring and should perhaps result in better human dynamics except when we look at the partner. Three Trial in low risk patients. These are the data in terms of moderate and severe mismatch at 30 days, and there were really no differences in both the tab, our group and the Surgery group, but importantly, the rates of moderate and severe mismatch were quite. We're still quite high in these patients, with almost a third of the patients leaving the hospital with moderate or severe mismatch. And in fact, at one year on Lee after surgery, when we looked at the human dynamics of the staff are and Savar valves in the Partner three trial, looking at patients that had Amy ingredient over 20. So in the moderate mismatch or in the moderate moderate stenosis, range 10% of the tab. Our group already had moderate stenosis one year only after surgery in the low risk trial. Remember, these patients were aged 74 at the time of surgery, so by no means where they even young adults at the time of intervention. And that rate was also pretty high in the surgical group, although half of what was observed in the tavern group with 5.5% rates of me ingredients over 20 millimeters of mercury. Importantly, one of the questions that comes up very regularly now is the role of Tab are in young adults on I would stay. There are still many, many unanswered questions and concerns in that patient population. Importantly, the safety and the suitability in unique husband and bicuspid aortic valves of using tab are there's a risk of stroke that may be higher. The impact of patient prosthesis mismatch off para valvular leaks of pacemaker implantation, all of which are higher with tab, are than in surgical valves, at least with current technology. Their impact in young adults is still unknown but thought to be more, uh, impactful than in elderly patients. There are obviously durability concerns, as I just showed you in the Partner three trial, and that these concerns may be, uh, amplified in younger adults because of accelerated degeneration. Recent data suggest that surgery after a previous cevaer is actually a much higher risk procedure than anticipated because these are often have to be converted into complex aortic root procedures. And recent data from the STS database suggested shows indicates a 20% mortality in patients undergoing Savar after a previous cevaer. And finally, coronary access issues in these patients, should they require coronary interventions in the future, is also a problem because of the mounted stent that may obstruct access to the coronary. So all of these air really unanswered questions that should be weighed very, very carefully and thoughtfully when addressing patients who come asking for tab our options, uh, under the age of 60 or under the age of 50. The second point as to why a prosthetic aortic valve replacement may result in higher mortality in the long term is the fact that the aortic root is a living structure. We often think of the aortic valve as a passive structure that opens and shuts in response to changes in trans valvular pressure. But the reality is that the aortic valve is much more sophisticated and complex than just a passive structure. I had the opportunity to spent four fabulous years with Sir Magdi Yakub doing a PhD in the many years ago. Now on the title of my PhD thesis was the living aortic valve. I spent four years in the lab looking and trying to understand the cellular, the molecular mechanisms of aortic valve function and dysfunction on how that relates to aortic root physiology and what we did understand or learn, and these air some of our findings, but really many other studies out there in the literature. But this is just a cross section of an aortic valve leaflet and it looks very much like a blood vessel. It has a mono layer of endothelial cells on both the Arctic and the ventricular side, and it has a mixed population of cells within the body of the leaflet, called interstitial cells, which have a contract out properties through smooth muscle cells, expressing expressing smooth muscle fact in as well as secretary properties with fibroblasts constantly Ramada Ling and renewing the extra cellular matrix. Very interestingly, the extra cellular matrix is very highly preserved between humans and across species, with mostly collagen on the Arctic side and mostly lasting on the ventricular side to allow that cusp to bear that diastolic clothes. All of this is in a leaflet which normally is about 300 microns in thickness, one third of a millimeter in thickness. It opens and closes over 100,000 times every single day. It adapts to changing human dynamic conditions constantly. It allows completely un obstructive laminar flow across the aortic root. It is a true work of genius, of creation or of nature, but really it is well beyond just a passive structure that opens and shuts, and therefore it's very hard to replicate all of these functions with a prosthetic, inert valve replacement. In fact, when we look even deeper into aortic valve cuts to see these you're a filaments in the body of the custom and their functions still remains very elusive. But their presence again testifies to the complexity and the connection between the aortic valve costs and the body both the neural hormonal elements circulating as well as the human dynamics, uh, to ensure optimal flow of blood and coronary flow reserve during the cardiac cycle. This is a study we performed in the lab where we took aortic valve caps from pig hearts. And we placed him in this by actual mechanical testing system to look at, relax ation and contraction properties of leaflets, but also to look at the changes in the elastic modulates or the stiffness of leaflets. And we discovered many phenomenal aspect of aortic valve cusp physiology. The first is what we call Anisotropy. The leaflets, the way they are formed and the way the cells and the extra cellular matrix is placed, allow for different mechanical properties along the circumferential access and the radial access of the leaflet. But mawr, interestingly, in that study. What we showed is that when we added different agents in the organ bath, the leaflets could change their stiffness. In response to these various agents when we added serotonin, the leaflets became much more relaxed when we inhibited the end Atheneum that leaflets became much stiffer, very similar to what happens with blood vessels with and ethereal dysfunction. And finally, when we added and the feel into the bath, mimicking a situation off primary hypertension, the leaflets became much stiffer, which again mimics a situation where the leaflets in the body would have to adapt to higher pressures by becoming a little bit stiffer to bear that higher diastolic clothes. So the reason I'm showing you just a snippet of what there is in the literature in terms of basic Val physiology is just to illustrate the fact that this living structure translates into many complex functions. For US clinicians, that means perfect laminar flow through a normal living trikus patriotic valve, excellent team of dynamics with no ingredients both at rest and with exercise low throw Magennis City. Because the serial cells can produce nitric oxide, which inhibits platelet aggregation and obviously good resistance to infections because these vows can easily mount an inflammatory reaction against bacteria should they be in the bloodstream and for our patients undergoing aortic valve replacement, all of these different elements the type of flow, the presence of mismatch, the need for anti coagulation or anti platelets resistance to infection. All of these things determine what we call clinically relevant end points such a survival, such as valve related complications and even such as quality of life. And so the idea is that, or the principle behind aortic valve surgery is that perhaps having a living aortic valve or a living aortic valve substitute in the Arctic position that would have unique biology and human dynamics would translate into improvements clinically relevant outcomes that I just mentioned earlier. And there are two ways to preserve biology and human dynamics across an aortic valve. The first is trying to repair the aortic valve if it's amenable to repair. And the second is to borrow the patient's own pulmonary valve, which is a mirror image of a normal aortic valve, and to place it in the aortic position. Therefore, implanting a living autologous tissue in the Arctic position, the so called Ross procedure. I'll spend just a couple of minutes talking about aortic valve repair on. I want to spend a bit more time this morning talking about the Ross procedure and its role in non elderly adults. But for those of you who are interested, this is a focus issue on advanced techniques in the aortic valve repair that really covers everything from image ing to surgical techniques to long term results that I had the opportunity to guest edit with Emmanuel non sack from Paris. Um, in a recent, uh, annals of cardiothoracic surgery issue, um, and we have summarized many of the concepts of bicuspid aortic valve repair. This is another review which I highly suggest that you read should you be interested in understanding the more the technical principles and the predictors of success or failure after aortic valve repair? Um, but this is just an illustration. This is the same patient that I showed you at the beginning of this presentation. Ah, 36 year old with bike husband, right, left fusion and severe eccentric aortic regurgitation, which is typically seen in these patients because of prolapse off that fuse leaflet. And this is what it looks like in the operating room, you can see the non fused leaflet. The non coronary has is not prolapse. Where's the fuse? Leaflet is prolapsed and we can fix that prolapsed by putting the central publications teachers on the fuse leaflets and you can see here the co optation is perfect. Um, the leaflets are, uh can be sucked together. The there's no more prolapse and we did the root replacement at the same time. And you can see on the echo here there's no residual jet off a I. So repair, particularly in bicuspid aortic valves, is a very reproducible technique. It all depends, or it all hinges on the quality of the leaflets present. If we have any diffuse calcification retraction, finished rations, all of these are, uh, poor predictors of repair ability and especially of durability of the repair. But leaflets like the ones that you saw here that are very pliable, very mobile, with no retraction, no ministrations, these air defense that we can very predictably, um, and reproducible e repair in patients and in terms of human dynamics, this is my personal Siris of aortic valve repair off close to 300 patients and you can see that me ingredients are under 10 millimeters of mercury, and they remain so over time there is no at least in the first decade, uh, structural value, the generation that appears, such as we see with tissue prosthesis and similarly, the in terms of cumulative incidence of aortic regurgitation. You can see that it's a, uh, it's about a 1% uh, incidence of recurrent AI and these patients. The rate of re operation is much lower, of course, because this can be tolerated for quite some time before patients need to be re operated. This is Johann Schaefer's. Siri's, probably the largest Siris in the literature of bicuspid aortic valve repair on, and it includes really the early experience as well, and you can see that survival is quite good at 15 years at 81% and that includes patients that were operated because of acute aortic dissection. But the question is, what do we do when the valve looks like this when it's full of calcium? Definitely not repairable, no pliability, no mobility left, and it needs to be replaced Well, what is the role of the Ross procedure in these patients? The Ross as I mentioned earlier is the only replacement operation that ensures long term viability of the aortic valve and route. It allows to have a living autologous tissue in the aortic position. And we have explains up to 30 and 40 years after the Ross procedure, showing that preserved try laminar structure with and cathedral cells on both sides with interstitial cells in the body of the leaflets. The Ross procedure is not a new operation. The original description was in 1967 by Donald Ross, a South African surgeon practicing in London, uh, at a time where mechanical valves were not available with where tissue valves were not available. So surgeons really had to think outside the box to try to find solutions. The only available replacement option at the time was was an aortic home, a graft, and we know that these used to calcify and wear out very quickly in young adults. And so the idea was that, perhaps borrowing that pulmonary valve, which is a mirror image of the aortic valve but the patient's own tissue would result in much better durability in the long term. It was really an ingenious uh um, bit of thinking from Donald Ross. And I'm sure some of you in the audience, particularly those who are around in the nineties, are thinking some of these things, whether I don't believe in the Ross procedure or all these patients come back for re operation. Or why don't we just put a large tissue valve and then do a valve involved in the future? I'll show you where some of these points may be overstated if we look objectively and carefully at the most recent literature long term literature with Ross procedure. Um, time will not allow me this morning to take a very deep dive into it. But for those of you who are interested, this is a recent state of the art review that we published in Jack about a couple of years ago. Both surgeons and cardiologists. You recognize some of the names? Uh, Dr Bono, Professor Yakub, Dr. David, um on it really covers all of the elements and everything that surrounds indications on long term outcomes. After the Ross procedure in adults, I will simply focus on survival this morning. The reason being that survival is a very binary outcome. You can't be half a life or half dead. You're either one or the other. It's very different than looking at N Y h A class or looking at a six minute walk test. This is really very hard data. Um, and this is one of the first study. I'll show you all of these air really studies published in the last decade or so. So quite recent literature and really a tsunami of literature on the Ross in the last 10 years. Um, it all started with this publication of this randomized trial, which Professor Yakub had undertaken in London in the late nineties, where he randomized young adults aged 38 on average at the time of surgery to undergo either a Ross procedure or an aortic home. A graft replacement, which at the time was thought to be the ideal substitute in young adults because of its excellent human dynamics. And these were really all comer patients. If we look carefully, 8% of the patients were operated on for Active and the card itis almost half the patients will redo procedures with, um um, almost a third of those being aortic home, a craft replacement. So by no means these were these easy operations and by no means where these patients expected to have very good long term outcomes, considering their previous more abilities or their active infection. And yet, when we looked at survival of these patients up to 13 years after surgery, you can see that in black, the Ross Cohort or sorry, the in black. The Ross cohort Survival was exactly identical to the UK agent. Sex matched general population. In contrast, patients undergoing a home a graft root replacement had survival that was significantly lower than the general population. So it really was the first study that showed using any valve substitute in the Arctic position for young adults restored survival versus the general population in the long term. And following publication of this study, many other groups analyze their long term data with Ross, and I'll show you some of these results. This is Tyrone David's experience from Toronto. Uh, just over 200 patients. The mean age was 34 at the time of surgery, and the mean follow up is 10 years. So again, pretty long durations of follow up, and you can see that up to 15 years survival of these patients is exactly identical to the Ontario Agent Sex Match general population. In fact, he updated his data a few years later with now a a median follow up of close to 14 years and looking at survival free from re operation. At 20 years, it was close to 75% which are excellent data in patients age 35 at the time of surgery. And that is even more so because this was mainly driven by re operation rather than death, as opposed to what I showed you earlier with prosthetic aortic valve replacement, where survival free from re operation was mainly driven by death rather than re operation. I'm sure if you ask any patient, they would much rather be alive and have to undergo a re operation than be dead and never have to undergo another intervention. Well, you may say this was Professor Yakub. On the one hand, this is Dr David, on the other hand, there, Master surgeons, what about the rest of us? While the Germans put all their data together into a German Ross registry and they published these data a few years ago off almost 1800 patients, the average age was 45 at the time of surgery and the mean follow up with eight years, with the third of these patients followed for more than 10 years. And what you see is that it up to 15 years again, survival of the patients is exactly identical to the German age and sex matched general population. And in fact, I just recently, uh, saw their updated results in that cohort now up to 25 years. And that survival remains similar to that of the general population up to 25 years after surgery. This is another study using UK National Data, a national registry of all patients undergoing aortic valve surgery between the age of 18 and 40 1500 patients. And they looked at survival free from re operation with Ross with the mechanical or with a tissue aortic valve replacement on again. Patients in the Rose Group performed far better than those in the mechanical group or than patients in the Tissue Aortic valve replacement group. And you'll notice that surprisingly, patients undergoing mechanical a VR had better results than those that underwent a tissue a VR. Despite the need for lifelong anti coagulation, this is yet another study recently published in Jack from Peter Skilling Teams Group in Australia, where they performed a propensity matched analysis of Ross procedure versus mechanical aortic valve replacement in patients aged 43 at the time of surgery. And they had 275 pairs. So pretty large number of patients and what they showed that 20 years was significantly better survival in the Ross Cohort versus the matched patients with undergoing Mechanical A VR with almost 10% difference and survival at 20 years. I'm sure that if you tell a 45 year old that they have a 10% higher chance of being alive 20 years down the line, but perhaps a slightly high risk of needing a re intervention during that time frame most patients will accept that proposition. And there are many more studies which are all listed in that jack review and in fact, somewhere that have been published since. And you can see that they come from different countries, different continents. The operative mortality is low. In all these studies, the mean follow up is all in the double digits and importantly, survival of these patients at 15 and 20 years after surgery is all identical to that of the age and sex matched general population. So there is a consistent signal that the Ross procedure seems to be the Onley operation that restores long term survival following replacement of the aortic valve. Now this sounds all very good. How come the Ross procedure is not more widely used? What is the Achilles heel of the Ross procedure, where there may be two reasons why it's not more widely used or it was, and it's been dropped off many centers. Menu one is surgical risk and complexity, and secondly, is our issues with durability. After a Ross procedure, mhm and to illustrate the safety of the operation, I'll just show you, um, my results from my previous group when I worked in Montreal, Um, where I performed close to over 750 aortic root reconstructive procedures so close to 500 Ross procedures now over 500 close to 300 aortic valve sparing or aortic valve repair procedures. And as you can see, we were a center that did not have a Ross program before I started in 2000 and 10, and that had a very meager aortic valve sparing or aortic valve repair program. So these all these results really, really includes my learning curve as a surgeon and as a raw surgeon. But importantly, we followed all our patients in the long term annually, with clinical and echocardiogram thick follow up, and that really allows us to inform everything that we do and to ensure that whatever we're doing actually translates into good long term outcomes on. I should really applaud the team that worked with me over there in ensuring that all these patients with followed annually this this was the cohort. The mean age was 48 years of age, and they were all comers. 15% were re operations. 58% of the patients had concomitant procedures, most frequently replacement of the ascending aorta. And 6% of the patients had active aortic valve endocarditis at the time of surgery. So again, not a terribly highly selected patient population, more oven, all comer patient population. And yet, despite our learning curve, being in their operative mortality was less than 0.5% in this cohort. In fact, if we look at the distribution over time, you can definitely see there's a learning curve because both mortalities occurred early in our Siri's and in the last almost seven plus years we have not had a single mortality in these patients despite and increase in our annual volumes of Ross procedures. And as I mentioned earlier, there is a learning curve. We had MAWR complications in the 1st 100 patients with patients requiring temporary dialysis patients requiring re exploration for bleeding and both mortalities in the Siri's. But in the last 400 or close to 400 patients, you can see that these complications have really become very rare and mortality has been almost eliminated in these patients. So it is a particularly safe operation if it is done, um, in, uh by dedicated surgeons with the rial interest, an understanding of the aortic root anatomy and physiology and this is our survival up to 10 years, you can see that it's exactly identical to the agent sex match general population again mirroring all the studies that I showed you earlier and importantly in terms of human dynamics, these are the main index effective orifice areas in the patients leaving the hospital. The main index effective orifice area was 1.5 centimeters squared by meter square with a range of 123 So not a single patient even close to the moderate mismatch range. The main ingredient at discharge was five millimeters of mercury, and as I mentioned, 0% of the patients had either moderate or severe mismatch. And this undoubtedly correlates with the survival data that we're seeing in the long term in these patients. And this is the evolution of greetings. Over time. We know that tissue a VRs degenerate as the years go by. A pulmonary autograph does not degenerate, and the greedy INTs remain low over time. It starts at around five and remains at around five up to 10 years after surgery and beyond. This is a study that we're currently performing called the Race Trial, where we're trying to understand beyond the issue of ingredients, how the left ventricle behaves and the health of the left ventricle. After Ross versus prosthetic aortic valve replacement patients are placed in an Emory machine and we look at strain and other measures of ventricular work. Uh, in patients would undergo undergone either Ross procedure or mechanical aortic valve replacement, and I do hope that we that this study provides meaningful insight to try to understand the differences in survival that we see after Ross versus prosthetic aortic valve replacement on the second issue I mentioned earlier is durability after the Ross procedure. And there are studies showing high rates of re operation on high failure rates after the Ross. This is a study from the Rotterdam group, which, as you see in patients older than 16 years of age at around seven years or so after surgery, can see a significant drop off. In durability of the operation, a lot of patients required re operation, usually because of autographed pulmonary autographed validation. But importantly, the same authors looked at these patients that came back for autographed re operation. And what they showed was that the majority most of the diameter increased was already reached at hospital discharge with diminished to increase thereafter. And what that tells us is that technique really matters with Ross procedure, and also that early delectation begets laid validation. So we really have to prevent that early validation and allowed the pulmonary autograph to adapt to its new human dynamic environment. And, as I said, earlier technique matters for all of cardiac surgery. But when it comes to the Ross. It matters in terms of safety of the operation. But it also matters in terms of the long term durability of the operation. And the Ross procedure has been there for over 50 years now, and we've had a chance to improve the techniques, but importantly, to learn from previous experience, what works and what does not work. And I think this, uh, paper that we recently published really summarizes all of the important technical key points to ensure excellent durability of the Ross in the long term. And it really all starts with understanding the anatomy or the differences in anatomy between the aortic valve and the pulmonary valve. You can see that the aortic root has a proper fibrous Angeles along a portion of the aortic analysts and that provides good structural support for the aortic valve. In fact, the aortic valve sits within the fiber skeleton of the heart, as opposed as opposed to what the pulmonary valve or where the pulmonary valve sits. The pulmonary valve is pushed upward by the infant tabular muscle. It does not sit within the fiber skeleton of the heart and, more importantly, does not have any fiber structure to support the pulmonary leaflets. There is no proper pulmonary Angeles as we see on the aortic side. And you can see here in this histological section, the pulmonary infant tabular muscle actually creeps into the base of the pulmonary artery. Now, remember, when we do the Ross we harvest this muscle here, which becomes the vascular rise becomes necrotic, and it provides no structural support to this pulmonary valve. One of the early mist aches that were made was to leave a long sleeve of muscle below the insertion of these leaflets onto just simply sutra to the Arctic annual ists. Therefore, sitting the pulmonary valve in a super annular position and then under systemic pressures that inevitably is at very high risk of dilating. So And I will not spend too much time talking about technical elements here because, um, this is not a purely surgical audience, but rather just highlight a few key points and this being really one of them that has been brought forth really in the last a decade or two when we really understood, uh, some of the failure mechanisms after the Ross. And so, technically speaking, what we have to do when we're doing the Ross is to implant the pulmonary autograph within the left ventricular outflow tract so that the native Aortic Angeles serves a support for the for the patients pulmonary valve. And this is just a quick illustration showing how the pulmonary valve has to be sad within the aortic annual ists, so that the native fibrous analyst then supports that pulmonary valve in the Arctic position and prevents any future debilitation. And importantly, we need to trim that muscle. You see here the pulmonary valves been harvested. We trim it, leaving no more than 2 to 3 millimeters, not a full centimeter like used to be done, but rather just very little in that. Because again, that muscle, once the valve is harvested, provides no structural support to the valve itself. The to place the valve in inside the Arctic annual C. C. The suitors on the Arctic side are placed deep in the L V o t. Much deeper than you would if you're simply replacing the valve with a prosthetic valve, and then the searcher has to go right at the hinge point off the pulmonary autographed. To exclude all of this infant tabular muscle when implanting the autographed. The distant future line of the autographed once implanted also have to be has to be carefully await. We should not leave any Super Commissioner pulmonary artery because under systemic pressures, this can also dilate. It can stretch this anti tubular junction and cause aortic regurgitation. And so the pulmonary autographed has to be trimmed a couple of millimeters above the commissioners and that should be included in the distant future line to stabilize the S T. J. And finally in patients with aortic regurgitation where the valve cannot be repaired. Uh, the operation has to be tailored in order to support that aortic root. There are different ways of doing so. There is an inclusion technique. Some surgeons have proposed putting it in a Dacron graft, which I don't think is the best approach because it really prevents the autographed on the Sinuses from keeping their dynamism, which is really the central component on advantage of this operation. Um, what we propose instead is to stabilize the aortic analysts and the Senate tubular junction in a way that prevents validation of both of these, and that has proven to be quite durable. over time and to do the aortic Aniela plastic. As you can see here, we take it background tube, from which we cut a ring of Dacron, which is sized according to the size of the pulmonary analysts and then the suitors, which were passed across the Arctic Annuals air, then passed across the Dacron ring. As you can see here, the ring is then lowered into position around the aortic Angelus, and the suitors are tied, as you can see around the Hagar dilator. And then once that is done, you can see that the Arctic analyst is now well supported. And the key element another key element for to ensure long term stability and durability of the Ross procedure is very strict control of blood pressure, not just while the patients are in the hospital, but really for the first 6 to 12 months to allow the autograph to adapt to its new systemic environment. And it's not enough to ensure that the patients leave the hospital. With the blood pressure under 110 millimeters systolic, we have implemented a system, um, off remote patient center, blood pressure monitoring, where patients have an app on their phones, and they are constantly communicating their Their, uh, blood pressure results to us. Any time we see the blood pressure exceed 110 for a couple of days in a row, we adjust the medication, and we keep the patients well controlled. And to our surprise, almost two thirds of the patients that leave the hospital with the blood pressure under 110 will require medication adjustments, particularly in the first 3 to 4 weeks after hospital discharge. So it's really critical to make sure that blood pressure is well controlled toe have a team around that does that because otherwise these autographs main dilate early, and as we know, this will be get laid debilitation. And this is just an example of a patient that had left the hospital with perfect blood pressure control as soon as they got home and they got more active. The blood pressure, as you can see, raised above 110. We adjusted the medication three times until we reached exactly where we wanted the pressure to be, and that is under 110 and you can see that from there on. It remained exactly where we wanted. And we have this graph for each and every one of our patients. Thanks to these, uh, this app system that we're using and that really allows us to follow these patients and to ensure durability. This is a propensity matched analysis of raw sources mechanical aortic valve replacement from the Toronto group using very robust A technique to do the Ross procedure. And interestingly, in terms of re operation, there were no differences between the Ross procedure and mechanical aortic valve replacement 20 years after surgery. So it really can be made into a very durable operation. And these are data from all of the studies that I mentioned earlier, Um, all of them showing freedom from re operation that is around, uh that is around the 1% patient year re operation range. So for patients in their thirties and forties, to have a 1% re operation range in the long term is actually very, very good. Durability does not mean that it cannot be improved on. I think that all of the latest, uh iterations that I showed you or modifications to the technique will continue to further improve durability of the operation in the long term, particularly in patients with aortic regurgitation. And my final point is, what about the guidelines? Well, the guidelines are supposed to align evidence and recommendation in a straight line. Yet when we look at the most recent a c c H A guidelines, the Ross is presented as a class to be indication. And on Lee, it may be considered in young patients when anti coagulation is contraindicated or undesirable. So it doesn't really correlate very well with all the data that I showed you both for Ross procedure and for mechanical erotic valve replacement. However, when we look at the references that were used to support this recommendation, you can see that none of the papers that I showed you earlier, including a prospective randomized trial in the land, set systematic reviews and meta analysis. None of it was referenced in the guidelines suggesting that either is some referencing bias or perhaps some oversight of these papers. But certainly if one were to evaluate these papers more carefully, the evidence would, and the recommendations would definitely change. When it comes to the Ross procedure, the European guidelines went about it a little differently. They simply do not mention the Ross procedure in their guidelines altogether. Uh, rather focusing simply on mechanical and tissue aortic valve replacement in young adults. So I would submit to you that the guidelines really do not a line evidence and recommendations at once. And one has to be a little bit more thoughtful when, uh, looking and evaluating these options and young adults. And in fact, in the in recent years, there have been many editorials now really supporting the notion that the Ross is probably the better alternative for these young patients. Um, you can see here. Tyrone Davis Editorial The Ross Procedure is the best operation to treat aortic stenosis, and young and middle aged adults from the Cleveland Clinic is a time to reconsider use of the Ross Procedure and adults and Michael Burger from Leipzig in Germany. The Ross procedure. Time to reevaluate the guidelines. So again, think back about these two scenarios that 53 year old with severe, isolated aortic stenosis or that 36 year old with my husband aortic regurgitation. Um, I think that the paradigm has really evolved when we see these patients in clinic. Now we cannot simply be thinking about anti coagulation versus re operation. Rather, we have to start thinking first about survival and quality of life. This should be the two metrics that we use in any patients under the age of 60 that presents to the office. How can I best normalize their survival and normalize their quality of life? And then we can look at all the other elements In summary, I think that in all non elderly adults, the type of surgery has a direct impact on long term prognosis. Prosthetic aortic valve replacement with a tissue or a mechanical valve is associated with excess long term mortality versus the general population. And this is due to the fact that a living aortic valve substitute provides unique biological and human dynamic features, which can translate into being done very safely. Justus safely as a conventional aortic valve replacement in centers of excellence with high volumes so similar operative risk. Importantly, it can restore late survival. It provides excellent quality of life, certainly better human dynamics with no patient prosthesis mismatch and also better freedom from valve related complications. We didn't go into it today for the interest of time, but certainly lower rates of endocarditis. Of course, no anti coagulation needed no from buying bolic risk because these air living valves and therefore there's no risk of blood clots forming on that on these cuffs. Um, in a recent editorial, we summarized our approach and Children and young adults. Uh, if the patients are suitable for Russ, repair should always be, uh, evaluated first. If it's not repairable, then, uh, we suggest that patients seek or are sent to a center that has Ross expertise to undergo a Ross procedure. Uh, and otherwise we suggest a tissue a VR for non from biogenic solutions, which, once the generated, would still be amenable to performing a Ross procedure as a redo operation. So with that, thank you again for being here this morning. Thank you for your attention. And I look forward to your questions.